REDUCTION OF COCAINE SELF ADMINISTRATION BY DOPAMINE D1 AGONISTS

点击翻译按钮获取中文摘要

Dopamine D1 agonists and partial agonists have pharmacological properties consistent with potential therapeutic utility in cocaine addiction The present study assessed the effects of D1 full agonists (SKF 82958, SKF 81297) and partial agonists (SKF 83959, SKF 77434, SKF 38393) on intravenous cocaine self-administration Squirrel monkeys were trained to self-administer cocaine on a second-order schedule of i v drug injection Initially, the effects of a full range of doses of self-administered cocaine were determined in each subject Subsequently, the effects of daily treatment with D1 agonists were determined on self-administration of doses of cocaine that maintained maximum rates of responding All D1 agonists, regardless of efficacy, suppressed cocaine self-administration in a dose-related manner, resulting in marked reductions in both response rate and injection frequency Daily treatment with effective doses of the D1 partial agonists SKF 83959 and SKF 7 7434 durin g re-determinations of the cocaine dose-response functions resulted in overall rightward and downward shifts of the functions In contrast, daily treatment with the D1 full agonists SKF 82958 and SKF 81297 produced downward shifts of the functions only In observational studies, SKF 83959 and SKF 77434 produced dose-related decreases in overall activity along with increases in species-typical sleep postures, but did not induce catalepsy or ataxia at doses 10-33 times greater than those required to suppress cocaine self-administration Only small changes in activity levels were observed with SKF 82958 and SKF 81297 The results show that D1 full and partial agonists are similarly effective in reducing self-administration of cocaine in monkeys, but can be distinguished on the basis of their capacity to alter the shape and position of the cocaine dose-response function and the incidence of sedative-like side effects These results suggest that D1 agonists are viable candidates for fu rther evaluation as pharmacotherapies for cocaine addiction PUBLICATIONS Platt DM, Rowlett JK and Spealman RD Suppression of cocaine self-administration by D1 partial agonists Soc Neurosci Abstr 24:2135, 1998